The present invention relates generally to novel compounds, their use in therapy, and pharmaceutical formulations containing them.
The amino acid tryptophan is converted biologically through the “kynurenine pathway” (Beadle, G. W., Mitchell, H. K., and Nyc, J. F., Proc. Nat. Acad. S C., 33, 155 (1948); see Charles Heidelberger, Mary E. Gullberg, Agnes Fay Morgan, and Samuel Lepkovsky TRYPTOPHAN METABOLISM. I. CONCERNING THE MECHANISM OF THE MAMMALIAN CONVERSION OF TRYPTOPHAN INTO KYNURENINE, KYNURENIC ACID, AND NICOTINIC ACID. J. Biol. Chem. (1949) 179: 143-150). Over 95% of all dietary tryptophan is metabolized to kynurenines (Wolf, H.—Studies on tryptophan metabolism in man. Scand J Clin Lab Invest 136(suppl.): 1-186, 1974). In peripheral tissues, in particular the liver, the indole ring of tryptophan is modified by either tryptophan dioxygenase or indoleamine 2,3-dioxygenase, which results in the formation of formylkynurenine. Kynurenine formylase then rapidly converts formylkynurenine to L-kynurenine, which is the key compound in the kynurenine pathway (W. Eugene Knox and Alan H. Mehler THE CONVERSION OF TRYPTOPHAN TO KYNURENINE IN LIVER. I. THE COUPLED TRYPTOPHAN PEROXIDASE-OXIDASE SYSTEM FORMING FORMYLKYNURENINE J. Biol. Chem. (1950)187: 419-430). L-kynurenine is present in low concentrations in the blood, the brain and in peripheral organs and it can easily cross the blood-brain barrier through the large neutral amino acid carrier. L-kynurenine is metabolized by three different enzymes in mammalian tissues: kynurenine 3-hydroxylase which form 3-hydroxy-kynurenine (3-HK); kynureninase which forms anthranilic acid and kynurenine aminotransferase (KAT) which causes the formation of kynurenic acid. 3-HK is metabolized by the same KAT to yield xanthurenic acid, a metabolically inert side product of the pathway, or by kynureninase to give rise to 3-hydroxyanthranilic acid, which is eventually converted to quinolinic acid. Finally, quinolinic acid is metabolized by quinolinic acid phosphoribosyltransferase, yielding nicotinic acid mononucleotide and subsequent degradation products including the end product NAD+.
Kynurenic acid, 3-hydroxykynurenine and quinolinic acid are all neuroactive intermediates of this catabolic cascade. 3-hydroxykynurenine is a free radical generator, which has been shown to cause induction of apoptosis, potentiation of excitotoxicity, cataract formation, neurodegenerative diseases, stroke, traumatic injury, neurovirological diseases and neuroinflammation. Quinolinic acid is an N-methyl-D-aspartate (NMDA) receptor agonist and free radical generator, and as such it can cause excitotoxicity, neurodegenerative diseases, stroke, traumatic brain injury, epilepsy, cerebral malaria, perinatal hypoxia, neurovirological diseases and neuroinflammation. Endogenous quinolinic acid might lead to NMDA receptoractivation to promote excitotoxicity and neurotoxicity leading to physiological and pathological processes that are mediated by NMDA receptors. Among the three neuroactive kynurenines, kynurenic acid (KYNA) has recently received the most attention. First described as a neuroinhibitory compound two decades ago, KYNA, at high, nonphysiological, concentrations is a broad-spectrum antagonist of ionotropic glutamate receptors. High concentrations of KYNA are anticonvulsant and provide excellent protection against excitotoxic injury. At much lower concentrations, KYNA acts as a competitive blocker of the glycine coagonist site of the NMDA receptor and as a noncompetitive inhibitor of the α7 nicotinic acetylcholine receptor. The fact that the affinity of KYNA to these two Ca2+-permeable receptors is in the range of KYNA levels in the human brain and reasonably close to the (lower) KYNA content of the rodent brain suggests a physiological function in glutamatergic and cholinergic neurotransmission. Direct support for such a role has been provided, for example, by in vivo studies in the rat striatum where a reduction in KYNA levels enhances vulnerability to an excitotoxic insult and, conversely, modest elevations of KYNA inhibit glutamate release (Schwarcz R, Pellicciari R. Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther. 2002 : 303:1-10).
Since kynurenines have been suggested to participate not only in the pathophysiology of neurodegenerative and seizure disorders, but also to play a role in a large number of etiologically diverse CNS diseases, it is important to modulate their formation. We propose that the 2-aminobenzoyl derivatives (kynurenine-like compounds) described here will be useful for such therapeutic intervention. Suggested mechanism of action could be, but is not limited to, by inhibiting enzymes in the kynurenine pathway, and/or inhibiting intermediate compounds, and/or inhibiting free radical formation.